The threat of terrorist attacks using biological weapons continues to be a major national security issue. A new congressional report (www.preventwmd.gov, Dec 3, 2008) indicates that a terrorist attack with bioweapons or other weapons of mass destruction might occur before 2013. Plague and smallpox could be devastating bioweapons if intentionally released. A release of 50 kg of Y. pestis over a city of 5 million people could result in as many as 150,000 clinical cases and 36,000 deaths. At this time, no human vaccines are available for plague and the current smallpox vaccine has significant side effects. Our long-term goal is to develop a highly safe and efficacious poxvirus-based vaccine that provides protection against aerosol exposure to Y. pestis and also against smallpox. As part of a phase 1-funded SBIR, we have optimized expression of Y. pestis antigens in the poxvirus vector, modified vaccinia virus Ankara (MVA) and evaluated the efficacy and safety profile of several recombinant MVA-based plague vaccines. As a result of these studies, we have selected for further development a recombinant MVA virus expressing a novel form of the Y. pestis V antigen (MVA/V). We propose here to manufacture GMP-quality vaccine seeds and conduct preclinical studies required for FDA approval under the Animal Rule (21 CFR, 314.600) and required to initiate human clinical trials. Our specific aims are: 1) develop master seed virus stocks for the MVA/V vaccine virus, 2) optimize the efficacy of MVA/V vaccine in mice, 3) determine the efficacy of a MVA/Vin two non-human primate species, 4) test for any toxicity of the MVA/V vaccine, and 5) develop quality control and release tests for GMP manufacturing of MVA/V. This project involves productive collaborations between a small business (Inviragen), research institutions (University of Wisconsin, Colorado State University), and government agencies (United States Army Medical Research Institute of Infectious Diseases, USGS National Wildlife Health Center). Inviragen's extensive experience with the manufacture, preclinical testing and regulatory submissions for recombinant viral vaccines will speed the progress of this needed product from the bench to the clinic. PUBLIC HEALTH RELEVANCE: Plague has caused severe epidemics in many parts of the world, resulting in human deaths and significant economic losses and could be a devastating bioweapon. The release of smallpox is a deadly bioterrorist threat given that much of the population is now unvaccinated. A safe, easily stored and easily administered combination vaccine that simultaneously protects against both plague and smallpox would improve the security and safety of military, first responder personnel and civilian populations worldwide.